The Nox enzymes represent a family of membrane enzymes (Nox1, Nox2, Nox3, Nox4, Nox5, Duox1 and Duox2) that catalyze NADPH-dependent generation of superoxide and/or hydrogen peroxide. These reactive oxygen species (ROS) can be further metabolized to other reactive products such as hypochlorous acide (HOCl) and peroxinitrite (HOONO). While the Nox enzymes have normal biological functions in signal transduction and host defense, they have also been implicated in the pathogenesis of a variety of diseases. Nox inhibitors and myeloperoxidase inhibitors have therapeutic uses and uses in biological assays. See Jaquet et al., 2009. Antioxid Redox Signal. 11(10):2535-52 and Malle et al., 2007, British Journal of Pharmacology 152(6):838-854.
The core catalytic domain of NOX enzymes share similar structure. The Nox enzymes' only known biochemical function is the generation of reactive oxygen species (ROS). The basic catalytic subunit of NOX contains a C-terminal dehydrogenase domain featuring a binding site for NADPH and bound flavin adenine nucleotide (FAD), as well as an N-terminal domain consisting of six trans-membrane helices that bind two heme groups. Upon enzyme activation, NADPH transfers its electron to the FAD, which in turn passes electrons sequentially to two hemes and ultimately to molecular oxygen to produce superoxide (O2—) and/or hydrogen peroxide (H2O2), depending upon the isoform. Although NOX-isoforms all catalyze the reduction of the molecular oxygen, they differ in their tissue distribution, their subunit requirement, domain structure, and mechanism by which they are activated. Depending upon the clinical condition, either isoform-selective, or Nox/Duox pan-specific inhibitors are contemplated to be useful for therapeutic applications. Potential Nox inhibitors have been investigated, such as diphenylene iodonium (DPI), apocynin, VAS2870, and pyrazolopyridines. There exists a need to identify inhibitors for Nox enzymes.
Much of the cell damage that arises from ROS is a result of further metabolism of the ROS to more reactive molecules. The ROS produced by Nox enzymes includes hydrogen peroxide, which is a substrate for the enzyme Myeloperoxidase (MPO. MPO catalyzes the reaction of hydrogen peroxide with a halide (e.g. chloride) to form a hypohalous acids (e.g., hypochlorite), or can react to oxidize a variety of other small molecules. MPO is implicated in causing a variety of oxidations and modifications of proteins, lipids and nucleic acids, and is thought to be a major form of ROS that causes cell damage and inflammation in a variety of diseases. MPO is expressed in neutrophils, macrophages and other cell types such as microglia where it plays a pathogenic role in disease states especially those involving inflammation. Both Nox enzymes and MPO are implicated in a wide range of diseases including acute lung inflammation, COPD, cystic fibrosis, Alzheimer's Disease, Parkinson's Disease, pulmonary hypertension, stroke, schizophrenia, traumatic brain injury, asbestos lung injury, multiple sclerosis, myocardial infarction, atherosclerosis, chronic heart failure, inflammatory bowel disease, asthma, cancer, and others. Thus MPO inhibitors are contemplated to be useful for therapeutic applications. Malle, et al. 2007 British Journal Pharmacology 152:838-854; Tiden et al. 2011. Journal of Biological Chemistry 286:37578-37589.
Certain quinazoline derivatives were identified in references. Hayao et al., J Med Chem 1965, 8:6, 807-11 disclose quinazoline derivatives produce vasodilation. See also U.S. Pat. No. 3,919,425. International PCT App. No. WO 2000/034278 discloses triazolo derivatives as chemokine inhibitors. US Patent App. No. 2009/0163545 discloses compounds for altering the lifespan of a eukaryotic organism identified using a DeaD assay.
References cited herein are not an admission of prior art.